# US 11,440,922 B2 · Heterocyclylmethylidene derivatives and their use as modulators of mGluR5 receptors

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- Number: US 11,440,922 B2
- Document ID: US11440922B2
- Status: Granted
- Kind: B2
- Application number: 16/500,128
- Filed: 2018-06-29
- Published: 2020-11-05
- Granted: 2022-09-13
- Earliest claimed: 2017-06-29
- Assignees: Recordati Industria Chimica e Farmacentica S.p.A.
- Applicants: Recordati Industria Chimica e Farmaceutica S.p.A.
- Inventors: Carlo Riva; Davide Graziani; Matteo Longhi; Elisa Callegari; Fabio Frigerio; Patrizia Angelico
- Web page: https://patentgrep.com/patent/US11440922B2

## CPC

- C07D 498/04: Ortho-condensed systems
- A61P 13/02: of urine or of the urinary tract, e.g. urine acidifiers
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- C07D 207/20: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 211/70: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 295/195: Radicals derived from nitrogen analogues of carboxylic acids
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 401/10: linked by a carbon chain containing aromatic rings
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 405/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 405/14: containing three or more hetero rings
- C07D 407/10: linked by a carbon chain containing aromatic rings
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 471/04: Ortho-condensed systems
- C07D 471/08: Bridged systems
- C07D 487/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

This invention relates to compounds of formula (I) and their use as allosteric modulators of mGluR5 receptor activity, pharmaceutical compositions containing the same, and methods of using the same as agents for the treatment and/or prevention of neurological and psychiatric disorders associated with glutamate dysfunction, such as schizophrenia or cognitive decline, dementia or cognitive impairment, or other pathologies that can be related directly or indirectly to glutamate dysfunction.

## Claims

### Claim 1

A compound of formula IA:
or an enantiomer, diastereomer, N-oxide, or a pharmaceutically acceptable salt or combinations thereof, wherein:
R1 is an optionally substituted monocyclic 6-membered aryl group or an optionally substituted monocyclic 6-membered heteroaryl group containing 1 or 2 nitrogen atoms;
A is a carbon-carbon triple bond;
R2 and R3 each represent an alkyl;
n is 0 or 1 and m is 1;
R4 is a carbonyl, a thiocarbonyl or a sulphonyl group, or a bond;
B is an oxygen or sulphur atom, a nitrogen atom optionally substituted by a C1-C5 alkyl group or a methoxy group, or B is absent;
R5 is an optionally substituted mono-, bi- or tricyclic C6-C14 aryl group, an optionally substituted mono-, bi- or tricyclic C1-C13 heterocyclic group containing from 1 to 5 heteroatoms selected from N, O and S, an optionally substituted C3-C6 cycloalkyl group, an optionally substituted C3-C6 cycloalkenyl group or an optionally substituted C1-C6 alkyl group; and R6 is a hydrogen atom, an optionally substituted C1-C4 alkyl group or a fluorine atom,
wherein the optional substituents are each independently selected from the group consisting of halogen atoms and C1-C6 alkyl, C1-C6 alkoxy, hydroxy, mercapto, nitro, cyano, oxo, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, C1-C6 alkylthio, C1-C6 alkylsulphonyl, C1-C6 alkylcarbonyl, sulphamoyl, C1-C6 alkylsulphamoyl, di(C1-C6)alkylsulphamoyl, (C1-C6)alkoxycarbonyl and (C1-C6)alkylcarbonyl(C1-C6)alkyl groups, and from groups of the formulae —NR*R*, —C(═O)—NR*R*, -A, —O-A, —C(═O)-A, —(CH2)q-A, —NR**-A, —C(═O)NR **-A, —NR **C(═O)-A and —O—C(═O)-A wherein each R* independently represents a hydrogen atom or a C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylcarbonyl, phenyl or benzyl group, R** represents a hydrogen atom or a C1-C6 alkyl group, q is an integer from 1 to 6 and A represents a phenyl group or a C1-C8 heterocyclic group containing from 1 to 3 heteroatoms selected from N, O and S; a C1-C6 cycloalkyl group; each group A being optionally substituted with from 1 to 3 groups independently selected from halo, hydroxy, cyano, nitro and C1-C6 alkyl.

### Claim 2 (depends on 1)

A compound according to claim 1 wherein the optional substituents are selected from the groups consisting of halogen atoms and C1-C6 alkyl groups; and R6 is a hydrogen atom, an optionally substituted C1-C4 alkyl group, or a fluorine atom.

### Claim 3 (depends on 1)

A compound according to claim 1, wherein R1 is selected from the group consisting of an optionally substituted phenyl, pyridinyl or pyrimidinyl moiety or derivative thereof.

### Claim 4 (depends on 1)

A compound according to claim 1, wherein R5 is selected from the group consisting of an optionally substituted methyl, ethyl, propyl, iso-propyl, tertiary-butyl, methoxyethyl, N,N-dimethyl, N-methoxy-N-methyl, N,N-diethyl, N-ethyl-N-isopropyl, cyclohexyl, benzotriazolyl, furanyl, isoxazolyl, morpholinyl, oxazolyl, phenyl, piperidinyl, pyranyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, triazinyl or triazolyl moiety or derivative thereof.

### Claim 5 (depends on 1)

A compound according to claim 1, wherein R4 is a carbonyl or sulphonyl group, B is absent and R5 is an optionally substituted bicyclic C1-C13 heterocyclic group containing from 1 to 5 heteroatoms selected from N, O and S.

### Claim 6 (depends on 1)

A compound according to claim 1, wherein B is an oxygen or nitrogen atom optionally substituted by a C1-C5 alkyl group or a methoxy group and R5 is selected from the group consisting of an optionally substituted methyl, ethyl, propyl, iso-propyl, tertiary-butyl or methoxyethyl moiety or derivative thereof.

### Claim 7 (depends on 1)

A compound according to claim 1, the compound being selected from the group consisting of:
1 tert-butyl (4E)-3,3-dimethyl-4-[3-(6-methylpyridin-2-yl)prop-2-yn-1-ylidene]piperidine-1-carboxylate;
1 tert-butyl (4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidine-1-carboxylate;
ethyl (4E)-3,3-dimethyl-4-[3-(6-methylpyridin-2-yl)prop-2-yn-1-ylidene]piperidine-1-carboxylate;
ethyl (4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidine-1-carboxylate;
tert-butyl (4E)-4-[3-(2-chloropyridin-4-yl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidine-1-carboxylate;
1 tert-butyl (4E)-3,3-dimethyl-4-[3-(3-methylphenyl)prop-2-yn-1-ylidene]piperidine-1-carboxylate;
ethyl (4E)-4-[3-(2-chloropyridin-4-yl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidine-1-carboxylate;
ethyl (4E)-3,3-dimethyl-4-[3-(3-methylphenyl)prop-2-yn-1-ylidene]piperidine-1-carboxylate;
ethyl (4E)-3,3-dimethyl-4-(3-phenylprop-2-yn-1-ylidene)piperidine-1-carboxylate;
ethyl (4E)-4-[3-(4-chloropyridin-2-yl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidine-1-carboxylate;
ethyl (4E)-4-[3-(2,5-difluorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidine-1-carboxylate;
ethyl (4E)-3,3-dimethyl-4-{3-[6-(trifluoromethyl)pyridin-2-yl]prop-2-yn-1-ylidene}piperidine-1-carboxylate;
ethyl (4E)-4-[3-(3-fluorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidine-1-carboxylate;
ethyl (4E)-3,3-dimethyl-4-{3-[3-(trifluoromethyl)phenyl]prop-2-yn-1-ylidene}piperidine-1-carboxylate;
ethyl (4E)-4-[3-(6-methoxypyridin-2-yl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidine-1-carboxylate;
ethyl (4E)-4-[3-(3-methoxyphenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidine-1-carboxylate;
ethyl (4E)-4-[3-(4-methoxypyridin-2-yl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidine-1-carboxylate;
ethyl (4E)-3,3-dimethyl-4-[3-(pyridin-2-yl)prop-2-yn-1-ylidene]piperidine-1-carboxylate;
ethyl (4E)-4-[3-(3-cyanophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidine-1-carboxylate;
ethyl (4E)-4-{3-[3-(cyanomethyl)phenyl]prop-2-yn-1-ylidene}-3,3-dimethylpiperidine-1-carboxylate;
ethyl (4E)-4-[3-(6-methoxypyridin-3-yl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidine-1-carboxylate;
ethyl (4E)-3,3-dimethyl-4-{3-[6-(methylamino)pyridin-2-yl]prop-2-yn-1-ylidene}piperidine-1-carboxylate;
ethyl (4E)-4-[3-(4-cyanopyridin-2-yl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidine-1-carboxylate;
ethyl (4E)-4-[3-(3-cyano-5-fluorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidine-1-carboxylate;
2-{(4E)-3,3-dimethyl-4-[3-(6-methylpyridin-2-yl)prop-2-yn-1-ylidene]piperidin-1-yl}-6-methyl-3-nitropyridine;
(3-chlorophenyl){(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}methanone;
{(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}(piperidin-1-yl)methanone;
{(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}(pyrrolidin-1-yl)methanone;
(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-N,N,3,3-tetramethylpiperidine-1-carboxamide;
(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-N,N-diethyl-3,3-dimethylpiperidine-1-carboxamide;
{(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}(furan-2-yl)methanone;
methyl (4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidine-1-carboxylate;
{(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}(morpholin-4-yl)methanone;
(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-N-methoxy-N,3,3-trimethylpiperidine-1-carboxamide;
{(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}(3-methylphenyl)methanone;
2-{(3E)-3-[1-(3-chlorobenzoyl)-3,3-dimethylpiperidin-4-ylidene]prop-1-yn-1-yl}pyridine-4-carbonitrile;
(3-chlorophenyl){(4E)-3,3-dimethyl-4-[3-(3-methylphenyl)prop-2-yn-1-ylidene]piperidin-1-yl}methanone;
(2,5-dimethylfuran-3-yl)[(4E)-4-{3-[3-(hydroxymethyl)phenyl]prop-2-yn-1-ylidene}-3,3-dimethylpiperidin-1-yl]methanone;
[(4E)-3,3-dimethyl-4-(3-{3-[(pyrrolidin-1-yl)methyl]phenyl}prop-2-yn-1-ylidene)piperidin-1-yl](5-methylfuran-2-yl)methanone;
ethyl (3E)-2,2-dimethyl-3-[3-(6-methylpyridin-2-yl)prop-2-yn-1-ylidene]pyrrolidine-1-carboxylate;
tert-butyl (3E)-2,2-dimethyl-3-[3-(6-methylpyridin-2-yl)prop-2-yn-1-ylidene]pyrrolidine-1-carboxylate;
propyl (3E)-2,2-dimethyl-3-[3-(6-methylpyridin-2-yl)prop-2-yn-1-ylidene]pyrrolidine-1-carboxylate;
2-methoxyethyl (3E)-2,2-dimethyl-3-[3-(6-methylpyridin-2-yl)prop-2-yn-1-ylidene]pyrrolidine-1-carboxylate;
2-methylpropyl (3E)-2,2-dimethyl-3-[3-(6-methylpyridin-2-yl)prop-2-yn-1-ylidene]pyrrolidine-1-carboxylate;
propan-2-yl (3E)-2,2-dimethyl-3-[3-(6-methylpyridin-2-yl)prop-2-yn-1-ylidene]pyrrolidine-1-carboxylate;
(3E)-N,N,2,2-tetramethyl-3-[3-(6-methylpyridin-2-yl)prop-2-yn-1-ylidene]pyrrolidine-1-carboxamide;
{(3E)-2,2-dimethyl-3-[3-(6-methylpyridin-2-yl)prop-2-yn-1-ylidene]pyrolidin-1-yl}(furan-2-yl)methanone;
(3-chlorophenyl){(3E)-2,2-dimethyl-3-[3-(6-methylpyridin-2-yl)prop-2-yn-1-ylidene]pyrrolidin-1-yl}methanone;
{(3E)-2,2-dimethyl-3-[3-(6-methylpyridin-2-yl)prop-2-yn-1-ylidene]pyrrolidin-1-yl)(piperidin-1-yl}methanone;
{(3E)-2,2-dimethyl-3-[3-(6-methylpyridin-2-yl)prop-2-yn-1-ylidene]pyrrolidin-1-yl}(pyrrolidin-1-yl)methanone;
methyl (3E)-2,2-dimethyl-3-[3-(6-methylpyridin-2-yl)prop-2-yn-1-ylidene]pyrrolidine-1-carboxylate;
tert-butyl (3E)-2,2-dimethyl-3-[3-(4-methylpyrimidin-2-yl)prop-2-yn-1-ylidene]pyrrolidine-1-carboxylate;
ethyl (3E)-2,2-dimethyl-3-[3-(4-methylpyrimidin-2-yl)prop-2-yn-1-ylidene]pyrrolidine-1-carboxylate;
2-methoxyethyl (3E)-2,2-dimethyl-3-[3-(4-methylpyrimidin-2-yl)prop-2-yn-1-ylidene]pyrrolidine-1-carboxylate;
propan-2-yl (3E)-2,2-dimethyl-3-[3-(4-methylpyrimidin-2-yl)prop-2-yn-1-ylidene]pyrrolidine-1-carboxylate;
methyl (3E)-2,2-dimethyl-3-[3-(4-methylpyrimidin-2-yl)prop-2-yn-1-ylidene]pyrrolidine-1-carboxylate;
tert-butyl (3E)-2,2-dimethyl-3-{3-[6-(methylamino)pyridin-2-yl]prop-2-yn-1-ylidene}pyrrolidine-1-carboxylate;
ethyl (3E)-2,2-dimethyl-3-{3-[6-(methylamino)pyridin-2-yl]prop-2-yn-1-ylidene}pyrrolidine-1-carboxylate;
propyl (3E)-2,2-dimethyl-3-{3-[6-(methylamino)pyridin-2-yl]prop-2-yn-1-ylidene}pyrrolidine-1-carboxylate;
2-methoxyethyl (3E)-2,2-dimethyl-3-{3-[6-(methylamino)pyridin-2-yl]prop-2-yn-1-ylidene}pyrrolidine-1-carboxylate;
2-methylpropyl (3E)-2,2-dimethyl-3-{3-[6-(methylamino)pyridin-2-yl]prop-2-yn-1-ylidene}pyrrolidine-1-carboxylate;
propan-2-yl (3E)-2,2-dimethyl-3-{3-[6-(methylamino)pyridin-2-yl]prop-2-yn-1-ylidene}pyrrolidine-1-carboxylate;
methyl (3E)-2,2-dimethyl-3-{3-[6-(methylamino)pyridin-2-yl]prop-2-yn-1-ylidene}pyrrolidine-1-carboxylate;
tert-butyl (3E)-3-[3-(4-cyanopyridin-2-yl)prop-2-yn-1-ylidene]-2,2-dimethylpyrrolidine-1-carboxylate;
ethyl (3E)-3-[3-(4-cyanopyridin-2-yl)prop-2-yn-1-ylidene]-2,2-dimethylpyrrolidine-1-carboxylate;
2-methoxyethyl (3E)-3-[3-(4-cyanopyridin-2-yl)prop-2-yn-1-ylidene]-2,2-dimethylpyrrolidine-1-carboxylate;
2-methylpropyl (3E)-3-[3-(4-cyanopyridin-2-yl)prop-2-yn-1-ylidene]-2,2-dimethylpyrrolidine-1-carboxylate;
propan-2-yl (3E)-3-[3-(4-cyanopyridin-2-yl)prop-2-yn-1-ylidene]-2,2-dimethylpyrrolidine-1-carboxylate;
methyl (3E)-3-[3-(4-cyanopyridin-2-yl)prop-2-yn-1-ylidene]-2,2-dimethylpyrrolidine-1-carboxylate;
tert-butyl (3E)-3-[3-(3-cyano-5-fluorophenyl)prop-2-yn-1-ylidene]-2,2-dimethylpyrrolidine-1-carboxylate;
ethyl (3E)-3-[3-(3-cyano-5-fluorophenyl)prop-2-yn-1-ylidene]-2,2-dimethylpyrrolidine-1-carboxylate;
propyl (3E)-3-[3-(3-cyano-5-fluorophenyl)prop-2-yn-1-ylidene]-2,2-dimethylpyrrolidine-1-carboxylate;
2-methoxyethyl (3E)-3-[3-(3-cyano-5-fluorophenyl)prop-2-yn-1-ylidene]-2,2-dimethylpyrrolidine-1-carboxylate;
2-methylpropyl (3E)-3-[3-(3-cyano-5-fluorophenyl)prop-2-yn-1-ylidene]-2,2-dimethylpyrrolidine-1-carboxylate;
propan-2-yl (3E)-3-[3-(3-cyano-5-fluorophenyl)prop-2-yn-1-ylidene]-2,2-dimethylpyrrolidine-1-carboxylate;
methyl (3E)-3-[3-(3-cyano-5-fluorophenyl)prop-2-yn-1-ylidene]-2,2-dimethylpyrrolidine-1-carboxylate;
tert-butyl (3E)-3-[3-(4-chloropyridin-2-yl)prop-2-yn-1-ylidene]-2,2-dimethylpyrrolidine-1-carboxylate;
{(3E)-3-[3-(4-chloropyridin-2-yl)prop-2-yn-1-ylidene]-2,2-dimethylpyrrolidin-1-yl}(furan-2-yl)methanone;
(3E)-3-[3-(4-chloropyridin-2-yl)prop-2-yn-1-ylidene]-N,N-diethyl-2,2-dimethylpyrrolidine-1-carboxamide;
{(3E)-3-[3-(4-chloropyridin-2-yl)prop-2-yn-1-ylidene]-2,2-dimethylpyrrolidin-1-yl}(pyrrolidin-1-yl)methanone;
{(3E)-3-[3-(4-chloropyridin-2-yl)prop-2-yn-1-ylidene]-2,2-dimethylpyrrolidin-1-yl}(piperidin-1-yl)methanone;
(3E)-3-[3-(4-chloropyridin-2-yl)prop-2-yn-1-ylidene]-N,N,2,2-tetramethylpyrrolidine-1-carboxamide;
ethyl (3E)-3-[3-(4-chloropyridin-2-yl)prop-2-yn-1-ylidene]-2,2-dimethylpyrrolidine-1-carboxylate;
methyl (3E)-3-[3-(4-chloropyridin-2-yl)prop-2-yn-1-ylidene]-2,2-dimethylpyrrolidine-1-carboxylate;
(3-chlorophenyl){(3E)-3-[3-(4-chloropyridin-2-yl)prop-2-yn-1-ylidene]-2,2-dimethylpyrrolidin-1-yl}methanone;
ethyl (3E)-3-[3-(6-aminopyridin-2-yl)prop-2-yn-1-ylidene]-2,2-dimethylpyrrolidine-1-carboxylate;
(3E)-3-[3-(6-aminopyridin-2-yl)prop-2-yn-1-ylidene]-N,N-diethyl-2,2-dimethylpyrrolidine-1-carboxamide;
methyl (3E)-3-[3-(6-aminopyridin-2-yl)prop-2-yn-1-ylidene]-2,2-dimethylpyrrolidine-1-carboxylate;
(3E)-3-[3-(6-aminopyridin-2-yl)prop-2-yn-1-ylidene]-N,N,2,2-tetramethylpyrrolidine-1-carboxamide;
tert-butyl (3E)-3-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-2,2-dimethylpyrrolidine-1-carboxylate;
{(3E)-3-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-2,2-dimethylpyrrolidin-1-yl}(piperidin-1-yl)methanone;
{(3E)-3-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-2,2-dimethylpyrrolidin-1-yl}(pyrrolidin-1-yl)methanone;
ethyl (3E)-3-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-2,2-dimethylpyrrolidine-1-carboxylate;
(3E)-3-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-N-ethyl-2,2-dimethyl-N-(propan-2-yl)pyrrolidine-1-carboxamide;
(3E)-3-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-N,N,2,2-tetramethylpyrrolidine-1-carboxamide;
{(3E)-3-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-2,2-dimethylpyrrolidin-1-yl}(furan-2-yl)methanone;
methyl (3E)-3-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-2,2-dimethylpyrrolidine-1-carboxylate;
(3-chlorophenyl){(3E)-3-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-2,2-dimethylpyrrolidin-1-yl}methanone;
(3-chlorophenyl)[(4E)-4-{[5-(3-chlorophenyl)-1H-pyrazol-3-yl]methylidene}-3,3-dimethylpiperidin-1-yl]methanone;
3-{(3E)-3-[1-(3-chlorobenzoyl)-3,3-dimethylpiperidin-4-ylidene]prop-1-yn-1-yl}benzonitrile;
3-{(3E)-3-[1-(3-chlorobenzoyl)-3,3-dimethylpiperidin-4-ylidene]prop-1-yn-1-yl}-5-fluorobenzonitrile;
(3-chlorophenyl){(4E)-4-[3-(3-methoxyphenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}methanone;
(3-chlorophenyl)[(4E)-4-{3-[3-(hydroxymethyl)phenyl]prop-2-yn-1-ylidene}-3,3-dimethylpiperidin-1-yl]methanone;
(3-chlorophenyl){(4E)-4-[3-(4-fluorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}methanone;
(3-chlorophenyl){(4E)-3,3-dimethyl-4-(3-β-[(pyrrolidin-1-yl)methyl]phenyl}prop-2-yn-1-ylidene)piperidin-1-yl]methanone;
(3-chlorophenyl){(4E)-3,3-dimethyl-4-[3-(6-methylpyridin-2-yl)prop-2-yn-1-ylidene]piperidin-1-yl}methanone;
5-{(3E)-3-[1-(3-chlorobenzoyl)-3,3-dimethylpiperidin-4-ylidene]prop-1-yn-1-yl}pyridine-2-carbonitrile;
(3-chlorophenyl){(4E)-4-[3-(6-methoxypyridin-3-yl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}methanone;
(3-chlorophenyl){(4E)-4-[3-(3-fluoro-5-hydroxyphenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}methanone;
{(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}(3-hydroxyphenyl)methanone;
{(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}(4-methoxypyridin-2-yl)methanone;
{(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}(6-methylpyridin-2-yl)methanone;
(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethyl-N-(6-methylpyridin-2-yl)piperidine-1-carboxamide;
{(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}(2,2-dimethylmorpholin-4-yl)methanone;
(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-N-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3,3-dimethylpiperidine-1-carboxamide;
(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethyl-N-(pyridin-2-yl)piperidine-1-carboxamide;
2-({(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}carbonyl)pyridine-4-carbonitrile;
1-{(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)ethanone;
{(4E)-4-[3-(3-Chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}(4-chloropyridin-2-yl)methanone;
{(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}(4,5-dimethylfuran-2-yl)methanone;
{(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}(3-methoxyphenyl)methanone;
3-({(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}carbonyl)benzonitrile;
(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-N-(4-chloropyridin-2-yl)-3,3-dimethylpiperidine-1-carboxamide;
2,2-dimethylpropyl (4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidine-1-carboxylate;
(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethyl-N-(3-methylphenyl)piperidine-1-carboxamide;
2-methylpyridin-4-yl (4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidine-1-carboxylate;
(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-N-(2,2-dimethylpropyl)-3,3-dimethylpiperidine-1-carboxamide;
{(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}(4-hydroxypiperidin-1-yl)methanone;
ethyl 4-({(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}sulfonyl)piperidine-1-carboxylate;
(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethyl-1-[(tetrahydro-2H-pyran-2-ylmethyl)sulfonyl]piperidine;
5-({(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}sulfonyl)-3-ethyl[1,2]oxazolo[5,4-b]pyridine;
(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethyl-1-{[(3-methyl-1,2-oxazol-5-yl)methyl]sulfonyl}piperidine;
(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-N,3,3-trimethyl-N-(propan-2-yl)piperidine-1-sulfonamide;
4-({(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}sulfonyl)-2,6-dimethylmorpholine;
(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethyl-1-(phenylsulfonyl)piperidine;
(4E)-N-tert-butyl-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidine-1-sulfonamide;
4-({(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}sulfonyl)morpholine;
4-({(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}sulfonyl)-1-methyl-1H-benzotriazole;
3-({(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}sulfonyl)-5-(propan-2-yloxy)pyridine;
(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-N-(cyclopropylmethyl)-N,3,3-trimethylpiperidine-1-sulfonamide;
5-({(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}sulfonyl)-2-methoxypyridine;
3-({(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}sulfonyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine;
(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-N-cyclohexyl-N,3,3-trimethylpiperidine-1-sulfonamide;
(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethyl-1-[(4-methylpiperidin-1-yl)sulfonyl]piperidine;
(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-1-[(2,2-dimethylpropyl)sulfonyl]-3,3-dimethylpiperidine;
(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethyl-1-[(tetrahydro-2H-pyran-3-ylmethyl)sulfonyl]piperidine;
(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-1-[(3,5-dimethyl-1,2-oxazol-4-yl)sulfonyl]-3,3-dimethylpiperidine;
6-({(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}sulfonyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile;
(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-1-[(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-3,3-dimethylpiperidine;
{(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}(4,6-dimethoxypyrimidin-2-yl)methanone;
{(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}(2-ethyl-5-methyl-2H-1,2,3-triazol-4-yl)methanone;
{(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}(4-methoxypyrimidin-2-yl)methanone;
{(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)methanone;
{(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}([1,2,4]triazolo[1,5-a]pyridin-2-yl)methanone;
{(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}(2,6-dimethoxypyrimidin-4-yl)methanone;
4-({(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}carbonyl)pyridine-2-carbonitrile;
{(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}(1,5-dimethyl-1H-1,2,3-triazol-4-yl)methanone;
{(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-3-yl)methanone;
6-({(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}carbonyl)pyridine-2-carbonitrile;
{(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}(3-methoxy-1-methyl-1H-pyrazol-5-yl)methanone;
(3-chlorophenyl){(4E)-4-[3-(4-methoxypyridin-2-yl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}methanone;
(3-chlorophenyl)[(4E)-4-{3-[5-(hydroxymethyl)furan-2-yl]prop-2-yn-1-ylidene}-3,3-dimethylpiperidin-1-yl]methanone;
(3-chlorophenyl)[(4E)-4-(3-cyclohexylprop-2-yn-1-ylidene)-3,3-dimethylpiperidin-1-yl]methanone;
(3-chlorophenyl){(4E)-4-[3-(4-chloropyridin-2-yl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}methanone;
(3-chlorophenyl)[(4E)-3,3-dimethyl-4-{3-[6-(trifluoromethyl)pyridin-2-yl]prop-2-yn-1-ylidene}piperidin-1-yl]methanone;
(3-chlorophenyl){(4E)-4-[3-(6-methoxypyridin-2-yl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}methanone;
(3-chlorophenyl){(4E)-4-[3-(3-hydroxyphenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}methanone;
[(4E)-3,3-dimethyl-4-(3-phenylprop-2-yn-1-ylidene)piperidin-1-yl](phenyl)methanone;
3-[(3E)-3-{1-[(2,5-dimethylfuran-3-yl)carbonyl]-3,3-dimethylpiperidin-4-ylidene}prop-1-yn-1-yl]benzonitrile;
{(4E)-4-[3-(3-chlorophenyl)prop-2-yn-1-ylidene]-3,3-dimethylpiperidin-1-yl}(phenyl)methanone;
3-{(3E)-3-[3,3-dimethyl-1-(3-methylbenzoyl)piperidin-4-ylidene]prop-1-yn-1-yl}benzonitrile;
3-{(3E)-3-[1-(3-methoxybenzoyl)-3,3-dimethylpiperidin-4-ylidene]prop-1-yn-1-yl}benzonitrile;
(4E)-4-{3-[3-(hydroxymethyl)phenyl]prop-2-yn-1-ylidene}-3,3-dimethyl-N-(6-methylpyridin-2-yl)piperidine-1-carboxamide; and
3-[(3E)-3-{1-[(2,5-dimethylfuran-3-yl)carbonyl]-3,3-dimethylpiperidin-4-ylidene}prop-1-yn-1-yl]-5-fluorobenzonitrile.

### Claim 8 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.

### Claim 9 (depends on 8)

A method for the treatment or prevention of a neurological or psychiatric disorder associated with glutamate dysfunction comprising administering to a subject in need of treatment an effective amount of a composition according to claim 8, wherein the disorder is selected from the group consisting of Fragile-X syndrome, Rett syndrome, Phelan-McDermid syndrome and tuberous sclerosis.

### Claim 10 (depends on 9)

A method according to claim 9, wherein the disorder is treatable or preventable by positive allosteric modulation (PAM) or by negative allosteric modulation (NAM) of mGluR5.

### Claim 11 (depends on 2)

A compound according to claim 2, wherein R1 is selected from the group consisting of an optionally substituted phenyl, pyridinyl or pyrimidinyl moiety or derivative thereof.

### Claim 12 (depends on 1)

A compound according to claim 1, wherein R1 is selected from the group consisting of an optionally substituted phenyl, pyridinyl or pyrimidinyl moiety or derivative thereof.

### Claim 13 (depends on 2)

A compound according to claim 2, wherein R5 is selected from the group consisting of an optionally substituted methyl, ethyl, propyl, iso-propyl, tertiary-butyl, methoxyethyl, N,N-dimethyl, N-methoxy-N-methyl, N,N-diethyl, N-ethyl-N-isopropyl, cyclohexyl, benzotriazolyl, furanyl, isoxazolyl, morpholinyl, oxazolyl, phenyl, piperidinyl, pyranyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, triazinyl or triazolyl moiety or derivative thereof.

### Claim 14 (depends on 1)

A compound according to claim 1, wherein R5 is selected from the group consisting of an optionally substituted methyl, ethyl, propyl, iso-propyl, tertiary-butyl, methoxyethyl, N,N-dimethyl, N-methoxy-N-methyl, N,N-diethyl, N-ethyl-N-isopropyl, cyclohexyl, benzotriazolyl, furanyl, isoxazolyl, morpholinyl, oxazolyl, phenyl, piperidinyl, pyranyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, triazinyl or triazolyl moiety or derivative thereof.

### Claim 15 (depends on 2)

A compound according to claim 2, wherein R4 is a carbonyl or sulphonyl group, B is absent and R5 is an optionally substituted bicyclic C1-C13 heterocyclic group containing from 1 to 5 heteroatoms selected from N, O and S.

### Claim 16 (depends on 1)

A compound according to claim 1, wherein R4 is a carbonyl or sulphonyl group, B is absent and R is an optionally substituted bicyclic C1-C13 heterocyclic group containing from to 5 heteroatoms selected from N, O and S.

### Claim 17 (depends on 2)

A compound according to claim 2, wherein B is an oxygen or nitrogen atom optionally substituted by a C1-C5 alkyl group or a methoxy group and R5 is selected from the group consisting of an optionally substituted methyl, ethyl, propyl, iso-propyl, tertiary-butyl or methoxyethyl moiety or derivative thereof.

### Claim 18 (depends on 1)

A compound according to claim 1, wherein B is an oxygen or nitrogen atom optionally substituted by a C1-C5 alkyl group or a methoxy group and R5 is selected from the group consisting of an optionally substituted methyl, ethyl, propyl, iso-propyl, tertiary-butyl or methoxyethyl moiety or derivative thereof.